Novel formulation of meloxicam

ABSTRACT

Unit dosage forms of meloxicam containing either 5 mg or 10 mg of meloxicam that provide effective pain relief and have desirable pharmacokinetic properties are described. The unit dosage forms can provide pain relief when a single unit dose is administered to a patient and useful for treating pain such as osteoarthritis pain at a relatively low systemic exposure to meloxicam.

RELATED APPLICATIONS

This application is a continuation and claims priority to U.S. patentapplication Ser. No. 16/689,032, filed on Nov. 19, 2019, which is acontinuation and claims priority to Ser. No. 15/802,771, filed on Nov.3, 2017, which is a continuation and claims priority to U.S. patentapplication Ser. No. 15/595,446, filed on May 15, 2017, which is acontinuation and claims priority to U.S. patent application Ser. No.14/974,108, filed on Dec. 18, 2015, which is a continuation and claimspriority to U.S. patent application Ser. No. 14/675,410, filed on Mar.31, 2015, which claims priority under 35 USC § 119(e) to provisionalU.S. Patent Application 62/009,860, filed on Jun. 9, 2014, the entirecontents of which is hereby incorporated by reference.

FIELD OF THE DISCLOSURE

The present disclosured relates to compositions comprising meloxicam,medicaments produced using meloxicam in particulate form and to methodsof treatment of an animal, including man, using a therapeuticallyeffective amount of meloxicam administered by way of such medicaments.Also described are methods for producing particles of meloxicam usingdry milling processes and processes for producing medicaments by furtherprocessing material produced by dry milling.

BACKGROUND

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treatacute and chronic pain, inflammation, and fever. Some of the activeagents in this class include aspirin, ibuprofen, naproxen, diclofenac,indomethacin, celecoxib, and meloxicam. Meloxicam was first approved formarketing in the U.S. in 2000 under the trade name Mobic® (BoehringerIngelheim). It is available as oral tablets (7.5 mg and 15 mg potencies)and as an oral suspension (7.5 mg/5 mL). Mobic is indicated for thetreatment of osteoarthritis, rheumatoid arthritis, and juvenilerheumatoid arthritis. The recommend starting and maintenance dose is 7.5mg per day. The maximum recommended daily dose is 15 mg per day. WhileNSAIDs have significant analgesic, anti-inflammatory, and antipyreticactivity, they are also associated with serious dose-related sideeffects such as gastrointestinal perforation and bleeding,cardiovascular events including myocardial infarction, and renalfailure. As a result, all FDA-approved NSAID products marketed in theUnited States, including meloxicam contain labeling statementsinstructing prescribing physicians to use the lowest effective dose forthe shortest possible duration. Thus, it is desirable to providetherapeutically effective NSAID products with drug doses that are lowerthan those currently available to patients suffering from acute orchronic pain.

Meloxicam is a member of the enolic acid group of NSAIDs and ischemically designated as4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.It is practically insoluble in water. Poor solubility is a significantproblem encountered in the development of compositions for thepharmaceutical, cosmetic, agricultural and food industries, particularlythose compositions containing a biologically active material that ispoorly soluble in water at physiological pH. In many instances, poorlysoluble compounds have undesirable pharmacokinetic properties such asslow dissolution and slow or incomplete oral absorption from thegastrointestinal tract to the systemic circulation. In addition, poorlysoluble active agents tend to be disfavored or even unsafe forintravenous administration due to the risk of particles of agentblocking blood flow through capillaries.

It is known that the rate of dissolution of a particulate drug willincrease with increasing surface area. One way of increasing surfacearea is decreasing particle size. Consequently, methods of making finelydivided or sized drugs have been studied with a view to controlling thesize and size range of drug particles for pharmaceutical compositions.

SUMMARY

Described herein are unit dosage forms of meloxicam containing either 5mg or 10 mg of meloxicam that provide effective pain relief and havedesirable pharmacokinetic properties. The unit dosage forms can providepain relief when a single unit dose is administered to a patient. Theunit dosage forms are useful for treating pain such as osteoarthritispain at a relatively low systemic exposure to meloxicam.

In some embodiments of the 5 mg unit dosage form described above, asingle dose, upon oral administration to a population of healthy adultsin the fasted state, provides a mean plasma AUC (0-∞) of 7500-20000h*ng/ml; a single dose, upon oral administration to a population ofhealthy adults in the fasted state, provides a mean plasma Cmax of400-900 ng/ml; a single dose, upon oral administration to a populationof healthy adults in the fasted state, provides a median Tmax of 1-3hours; a single dose, upon oral administration to a population ofhealthy adults in the fasted state, provides a mean plasma AUC (0-∞)that is 80% to 125% of 13610 ng-h/ml; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean plasma Cmax that is 80% to 125% of 642 ng/ml.

Described herein is a solid unit dosage form of a pharmaceuticalcomposition comprising 5 mg of meloxicam and one or morepharmaceutically acceptable excipients, wherein the particles ofmeloxicam have a median particle size, on a volume average basis,between 100 nm and 5000 nm. In various cases: the D(0.9) of theparticles of meloxicam is less than 3000 nm; the surface weighted meandiameter (D[3,2]) of the particles of meloxicam is between 100 nm and800 nm; volume weighted mean diameter (D[4,3]) of the particles ofmeloxicam is between 400 nm and 1300 nm; the dissolution rate of theunit dosage from is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 500 mL of pH 6.1 phosphatebuffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5° C., at least80% of the meloxicam dissolves in a time period selected from: 30minutes or less; 20 minutes or less; 10 minutes or less; and 5 minutesor less. In other cases the dissolution rate of the unit dosage form issuch that, when tested using USP Apparatus 1 (baskets) set to rotationspeed of 100 RPM in 500 mL of pH 6.1 phosphate buffer with 0.1% sodiumlauryl sulfate (SLS) at 37° C.±0.5° C., at least 90% of the meloxicamdissolves in a time period selected from: 30 minutes or less; 20 minutesor less; 10 minutes or less; and 5 minutes or less. In various cases: asingle dose, upon oral administration to a population of healthy adultsin the fasted state, provides a mean blood plasma AUC (0-∞) of7500-20000 h*ng/ml; a single dose, upon oral administration to apopulation of healthy adults in the fasted state, provides a mean bloodplasma Cmax of 400-900 ng/ml; a single dose, upon oral administration toa population of healthy adults in the fasted state, provides a meanblood plasma Cmax of 400-900 ng/ml; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean blood plasma AUC (0-∞) of 7500-20000 h*ng/ml; a singledose, upon oral administration to a population of healthy adults in thefasted state, provides a mean blood plasma AUC (0-∞) that is 80% to 125%of 13610 ng-h/ml; a single dose, upon oral administration to apopulation of healthy adults in the fasted state, provides a mean bloodplasma Cmax that is 80% to 125% of 642 ng/ml.

Also described herein is a solid unit dosage form of a pharmaceuticalcomposition comprising 5 mg of meloxicam, wherein a single dose, uponoral administration to a population of healthy adults in the fastedstate, provides a mean blood plasma Cmax of 350-950 ng/ml. Alsodescribed is a solid unit dosage form of a pharmaceutical compositioncomprising 5 mg of meloxicam, wherein a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean blood plasma AUC (0-∞) of 7500-20000 h*ng/ml. In variouscases of these dosage forms: the particles of meloxicam have a medianparticle size, on a volume average basis, between 100 nm and 5000 nm. Invarious cases: the D(0.9) of the particles of meloxicam is less than3000 nm; the surface weighted mean diameter (D[3,2]) of the particles ofmeloxicam is between 100 nm and 800 nm; and volume weighted meandiameter (D[4,3]) of the particles of meloxicam is between 400 nm and1300 nm.

In some embodiments of the 5 mg unit dosage form described above, thedissolution rate of the unit dosage form is such that, when tested usingUSP Apparatus 1 (baskets) set to rotation speed of 100 RPM in 500 mL ofpH 6.1 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37°C.±0.5° C., at least 80% of the meloxicam dissolves in a time periodselected from: 30 minutes or less; 20 minutes or less; 10 minutes orless; and 5 minutes or less. In other cases the dissolution rate of theunit dosage form is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 500 mL of pH 6.1 phosphatebuffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5° C., at least90% of the meloxicam dissolves in a time period selected from: 30minutes or less; 20 minutes or less; 10 minutes or less; and 5 minutesor less.

In some embodiments of the 5 mg unit dosage form: the dissolution rateis such that, when tested using USP Apparatus 1 (baskets) set torotation speed of 100 RPM in 500 mL of pH 6.1 phosphate buffer with 0.1%sodium lauryl sulfate (SLS) at 37° C.±0.5° C., at least 90% of themeloxicam dissolves in 30 minutes; at least 90% of the meloxicamdissolves in 20 minutes; at least 90% of the meloxicam dissolves in 10minutes; at least 95% of the meloxicam dissolves in 30 minutes; at least95% of the meloxicam dissolves in 20 minutes; at least 95% of themeloxicam dissolves in 10 minutes; at least 70% of the meloxicamdissolves in 5 minutes.

In some embodiments of the 5 mg unit dosage form: the mean Cmax of asingle unit is within 80.00% to 125.00% of the mean Cmax of 7.5 mg Mobictablets, when a single unit is administered to a population of healthyadults in the fasted state; a single unit, upon oral administration to apopulation of healthy adult patients in the fasted state, provides amean blood plasma AUC (0-∞) hours that is 60%-80% of the mean bloodplasma AUC (0-∞) hours of 7.5 mg Mobic tablets, when a single dose isadministered to a population of healthy adults in the fasted state; theunit dosage form is a capsule or a tablet; the unit dosage form is ahard gelatin capsule.

In various cases: a single dose, upon oral administration to apopulation of healthy adults in the fasted state, provides a mean bloodplasma AUC (0-∞) of 7500-20000 h*ng/ml; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean blood plasma Cmax of 400-900 ng/ml; a single dose, uponoral administration to a population of healthy adults in the fastedstate, provides a mean blood plasma Cmax of 400-900 ng/ml; a singledose, upon oral administration to a population of healthy adults in thefasted state, provides a mean blood plasma AUC (0-∞) of 7500-20000h*ng/ml; a single dose, upon oral administration to a population ofhealthy adults in the fasted state, provides a mean blood plasma AUC(0-∞) that is 80% to 125% of 13610 ng-h/ml; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean blood plasma Cmax that is 80% to 125% of 642 ng/ml.

Also described herein is a unit dosage form comprising 10 mg ofmeloxicam. In some embodiments, a single dose, upon oral administrationto a population of healthy adults in the fasted state, provides a meanplasma AUC (0-∞) of 16000-44000 h*ng/ml; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean plasma Cmax of 850-1750 ng/ml; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a median plasma Tmax of 1 to 3 hrs; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean plasma AUC (0-∞) that is 80% to 125% of 29,173 ng-h/ml;a single dose, upon oral administration to a population of healthyadults in the fasted state, provides a mean plasma Cmax that is 80% to125% of 1253 ng/ml.

In some embodiments, the dissolution rate of the 10 mg unit dosage formis such that, when tested using USP Apparatus 1 (baskets) set torotation speed of 100 RPM in 1000 mL of pH 6.1 phosphate buffer with0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5° C., at least 80% of themeloxicam dissolves in a time period selected from: 30 minutes or less;20 minutes or less; 10 minutes or less; and 5 minutes or less; thedissolution rate is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 1000 mL of pH 6.1phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5°C., at least 90% of the meloxicam dissolves in a time period selectedfrom: 30 minutes or less; 20 minutes or less; 10 minutes or less; and 5minutes or less. and one or more pharmaceutically acceptable excipients,wherein the particles of meloxicam have a median particle size, on avolume average basis, between 100 nm and 5000 nm. In various cases: theD(0.9) of the particles of meloxicam is less than 3000 nm; the surfaceweighted mean diameter (D[3,2]) of the particles of meloxicam is between100 nm and 800 nm; the volume weighted mean diameter (D[4,3]) of theparticles of meloxicam is between 400 nm and 1300 nm; the dissolutionrate of the unit dosage form is such that, when tested using USPApparatus 1 (baskets) set to rotation speed of 100 RPM in 500 mL of pH6.1 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37°C.±0.5° C., at least 80% of the meloxicam dissolves in a time periodselected from: 30 minutes or less; 20 minutes or less; 10 minutes orless; and 5 minutes or less; the dissolution rate is such that, whentested using USP Apparatus 1 (baskets) set to rotation speed of 100 RPMin 500 mL of pH 6.1 phosphate buffer with 0.1% sodium lauryl sulfate(SLS) at 37° C.±0.5° C., at least 90% of the meloxicam dissolves in atime period selected from: 30 minutes or less; 20 minutes or less; 10minutes or less; and 5 minutes or less; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a median blood plasma tmax of 1 to 3 hrs; a single dose, uponoral administration to a population of healthy adults in the fastedstate, provides a mean blood plasma AUC (0-∞) of 16000-44000 h*ng/ml; asingle dose, upon oral administration to a population of healthy adultsin the fasted state, provides a mean blood plasma Cmax of 850-1750ng/ml; a single dose, upon oral administration to a population ofhealthy adults in the fasted state, provides a mean blood plasma AUC(0-∞) that is 80% to 125% of 29,173 ng-h/ml; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean blood plasma Cmax that is 80% to 125% of 1253 ng/ml.

Also described herein is a solid unit dosage form of a pharmaceuticalcomposition comprising 10 mg of meloxicam and one or morepharmaceutically acceptable excipients wherein a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean blood plasma AUC (0-∞) of 16000-44000 h*ng/ml. Alsodescribed herein is a unit dosage form of a pharmaceutical compositioncomprising 10 mg of meloxicam and one or more pharmaceuticallyacceptable excipients wherein a single dose, a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean blood plasma Cmax of 850-1750 ng/ml. In variousembodiments: the particles of meloxicam have a median particle size, ona volume average basis, between 100 nm and 5000 nm. In various cases:the D(0.9) of the particles of meloxicam is less than 3000 nm; thesurface weighted mean diameter (D[3,2]) of the particles of meloxicam isbetween 100 nm and 800 nm; the volume weighted mean diameter (D[4,3]) ofthe particles of meloxicam is between 400 nm and 1300 nm; thedissolution rate of the unit dosage form is such that, when tested usingUSP Apparatus 1 (baskets) set to rotation speed of 100 RPM in 500 mL ofpH 6.1 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37°C.±0.5° C., at least 80% of the meloxicam dissolves in a time periodselected from: 30 minutes or less; 20 minutes or less; 10 minutes orless; and 5 minutes or less; the dissolution rate is such that, whentested using USP Apparatus 1 (baskets) set to rotation speed of 100 RPMin 500 mL of pH 6.1 phosphate buffer with 0.1% sodium lauryl sulfate(SLS) at 37° C.±0.5° C., at least 90% of the meloxicam dissolves in atime period selected from: 30 minutes or less; 20 minutes or less; 10minutes or less; and 5 minutes or less; a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a median blood plasma tmax of 1 to 3 hrs; a single dose, uponoral administration to a population of healthy adults in the fastedstate, provides a mean blood plasma AUC (0-∞) that is 80% to 125% of29,173 ng-h/ml; a single dose, upon oral administration to a populationof healthy adults in the fasted state, provides a mean blood plasma Cmaxthat is 80% to 125% of 1253 ng/ml.

In the case of the solid unit dosage forms containing 10 mg ofmeloxicam, in some embodiments: a single dose, upon oral administrationto a population of healthy adults in the fed state, provides a meanblood plasma Cmax of 525-1500 ng/ml; a single dose, upon oraladministration to a population of healthy adults in the fed state,provides a median blood plasma tmax of 3 to 7 hrs; a single dose, uponoral administration to a population healthy adults in the fed state,provides a mean blood plasma AUC (0-∞) of 15000-42000 h*ng/ml; a singledose, upon oral administration to a population of healthy adults in thefed state, provides a mean blood plasma Cmax that is 80% to 125% of27,146 ng/ml.

In some embodiments of the 5 mg and 10 mg unit dosage forms describedabove the particles of meloxicam have a median particle size, determinedon a particle volume basis, that is greater than 100 nm and is equal orless than a size selected from the group consisting of 5000 nm, 4500 nm,4000 nm, 3000 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm,1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600nm, 500 nm, 400 nm, 300 nm, and 200 nm In some embodiments, the D90 ofthe particle size distribution, as measured on a particle volume basis,is selected from the group consisting of less than or equal, 4000 nm,3000 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm,1300 nm, 1200 nm, 1100 nm, or 1000 nm and, in some cases, greter than900 nm.

In some embodiments of the 5 mg unit dosage form: the dissolution rateis such that, when tested using USP Apparatus 1 (baskets) set torotation speed of 100 RPM in 500 mL of pH 6.1 phosphate buffer with 0.1%sodium lauryl sulfate (SLS) at 37° C.±0.5° C., at least 90% of themeloxicam dissolves in 30 minutes; the dissolution rate is such that,when tested using USP Apparatus 1 (baskets) set to rotation speed of 100RPM in 500 mL of pH 6.1 phosphate buffer with 0.1% sodium lauryl sulfate(SLS) at 37° C.±0.5° C., at least 90% of the meloxicam dissolves in 20minutes; the dissolution rate is such that, when tested using USPApparatus 1 (baskets) set to rotation speed of 100 RPM in 500 mL of pH6.1 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37°C.±0.5° C., at least 90% of the meloxicam dissolves in 10 minutes; thedissolution rate is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 500 mL of pH 6.1 phosphatebuffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5° C., at least95% of the meloxicam dissolves in 30 minutes; the dissolution rate issuch that, when tested using USP Apparatus 1 (baskets) set to rotationspeed of 100 RPM in 500 mL of pH 6.1 phosphate buffer with 0.1% sodiumlauryl sulfate (SLS) at 37° C.±0.5° C., at least 95% of the meloxicamdissolves in 20 minutes; the dissolution rate is such that, when testedusing USP Apparatus 1 (baskets) set to rotation speed of 100 RPM in 500mL of pH 6.1 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at37° C.±0.5° C., at least 95% of the meloxicam dissolves in 10 minutes;the dissolution rate is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 500 mL of pH 6.1 phosphatebuffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5° C., at least70% of the meloxicam dissolves in 5 minutes;

In some embodiments of the 5 mg unit dosage form: the 90% CI of the meanCmax of a single unit is within 80.00% to 125.00% of the mean Cmax of7.5 mg Mobic tablets, when a single unit is administered to an adult inthe fasted state; a single unit, upon oral administration to an adultpatient in the fasted state, provides a mean blood plasma AUC (0-48)hours that is 70%-85% of the mean blood plasma AUC (0-48) hours of 7.5mg Mobic tablets, when a single dose is administered to an adult in thefasted state; the unit dosage from is a capsule or a tablet; the unitdosage form is a hard gelatin capsule.

In some embodiments of the 10 mg dosage form: the dissolution rate issuch that, when tested using USP Apparatus 1 (baskets) set to rotationspeed of 100 RPM in 1000 mL of pH 6.1 phosphate buffer with 0.1% sodiumlauryl sulfate (SLS) at 37° C.±0.5° C., at least 90% of the meloxicamdissolves in 30 minutes; the dissolution rate is such that, when testedusing USP Apparatus 1 (baskets) set to rotation speed of 100 RPM in 1000mL of pH 6.1 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at37° C.±0.5° C., at least 90% of the meloxicam dissolves in 20 minutes;the dissolution rate is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 1000 mL of pH 6.1phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5°C., at least 90% of the meloxicam dissolves in 10 minutes; thedissolution rate is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 1000 mL of pH 6.1phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5°C., at least 95% of the meloxicam dissolves in 30 minutes; thedissolution rate is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 1000 mL of pH 6.1phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5°C., at least 95% of the meloxicam dissolves in 20 minutes; thedissolution rate is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 1000 mL of pH 6.1phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5°C., at least 95% of the meloxicam dissolves in 10 minutes; thedissolution rate is such that, when tested using USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 1000 mL of pH 6.1phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5°C., at least 70% of the meloxicam dissolves in 5 minutes; the 90% CI ofthe mean Cmax is with 80.00% to 125.00% of the mean Cmax of 15 mg Mobictablets, when a single unit is administered to a population of healthyadults in the fasted state; a single unit, upon oral administration to apopulation of healthy adults in the fasted state, provides a mean bloodplasma AUC (0-∞) hours that is 60%-80% of the mean blood plasma AUC(0-∞) hours of 15 mg Mobic tablets, when a single unit is administeredto a population of healthy adults in the fasted state; the unit dosageform is a capsule or a tablet; the unit dosage form is a hard gelatincapsule.

In some embodiments of the 5 mg and 10 mg unit dosage forms describedabove the particles of meloxicam have a median particle size, determinedon a particle volume basis, that is greater than 100 nm and is equal orless than a size selected from the group consisting of 5000 nm, 4500 nm,4000 nm, 3000 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm,1400 nm, 1300 nm, 1200 nm, 1100 nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600nm, 500 nm, 400 nm, 300 nm, and 200 nm. In some embodiments, the D90 ofthe particle size distribution, as measured on a particle volume basis,is selected from the group consisting of less than or equal, 4000 nm,3000 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm,1300 nm, 1200 nm, 1100 nm, or 1000 nm and, in some cases, greter than900 nm. In some embodiments the surface weighted mean diameter (D[3,2])of the particles of meloxicam is between 100 nm and 800 nm; in someembodiments the volume weighted mean diameter (D[4,3]) of the particlesof meloxicam is between 400 nm and 1300 nm.

Pharmacokinetic testing in human subjects demonstrated that single dosesof the 5 mg and 10 mg unit dosages of the present invention were morerapidly absorbed than a 15 mg dosage of Mobic when all test articleswere taken in the fasted state. The median time to maximum plasmaconcentration (Tmax) for the 5 mg and 10 mg dosages was 2 hours, whilethe median time to Tmax for the 15 mg Mobic tablet was 4 hours. Thetesting also demonstrated that a single dose of the 10 mg unit dosageform exhibited about ⅓ lower systemic exposure (AUC) compared to asingle dose of a conventional 15 mg Mobic® tablet. Based on thedose-proportionality of the 10 mg and 5 mg dosage forms describedherein, it is expected that the 5 mg dosage form will exhibit about ⅓lower systemic exposure compared to conventional 7.5 mg Mobic® tablets.Despite the lower systemic exposure observed for a single dose of the 10mg dosage form compared to a single dose of the conventional 15 mgMobic® tablet, the peak plasma concentration (Cmax) observed for asingle dose of the 10 mg dosage form was comparable to that of a singledose of the conventional 15 mg Mobic® tablet.

The unit dosage forms described herein can be used to treat pain, e.g.,pain associated with arthritis, e.g, osteoarthritis or rheumatoidarthritis. In some embodiments, the unit dosage is a solid dosage form.In some embodiments, the unit dosage comprises 5 mg or 10 mg ofmeloxicam and one or more pharmaceutically acceptable excipients.

The 5 mg unit dosage form can be administered 1 to 5 times daily with asingle unit each time for a total dose of 5 mg for each administration.Alternatively, two units of the 5 mg unit dosage form can beadministered 1 to 5 times daily with a single unit each time for a totaldose of 5 mg for each administration.

The 10 mg unit dosage form can be administered 1 to 5 times daily with asingle unit each time for a total dose of 10 mg for each administration.

In some cases, the crystallinity profile of the meloxicam in the dosageform is selected from the group consisting of: at least 20% of thebiologically active material is crystalline, at least 30% of thebiologically active material is crystalline, at least 40% of thebiologically active material is crystalline, at least 50% of thebiologically active material is crystalline, at least 60% of thebiologically active material is crystalline, at least 70% of thebiologically active material is crystalline, at least 75% of thebiologically active material is crystalline, at least 85% of thebiologically active material is crystalline, at least 90% of thebiologically active material is crystalline, at least 95% of thebiologically active material is crystalline and at least 98% of thebiologically active material is crystalline. In some cases, thecrystallinity profile of the biologically active material issubstantially equal to the crystallinity profile of the biologicallyactive material before the material was subjected to the method asdescribed herein.

The disclosure also includes methods for dry milling meloxicam inpresence of a plurality of milling bodies, a millable grinding matrix,and a facilitating agent, e.g., a surfactant.

In some embodiments, the milling time period is a range selected fromthe group consisting of: between 10 minutes and 3 hours, between 10minutes and 2.5 hours, between 10 minutes and w hours, between, between20 minutes and 2 hours, between 20 minutes and 90 minutes, and between30 minutes and 90 minutes.

In some embodiments, the milling bodies are formed of a material isselected from the group consisting of: ceramics, glasses, polymers,ferromagnetics and metals. In some cases, the milling bodies are steelballs having a diameter selected from the group consisting of: between 1and 20 mm, between 2 and 15 mm and between 3 and 10 mm. In some cases,the milling bodies are zirconium oxide balls having a diameter selectedfrom the group consisting of: between 1 and 20 mm, between 2 and 15 mmand between 3 and 10 mm. In some embodiments, the dry milling apparatusis a mill selected from the group consisting of: attritor mills(horizontal or vertical), nutating mills, tower mills, pearl mills,planetary mills, vibratory mills, eccentric vibratory mills,gravity-dependent-type ball mills, rod mills, roller mills and crushermills. In some cases, the milling bodies within the milling apparatusare mechanically agitated by 1, 2 or 3 rotating shafts. In some cases,the method is configured to produce the biologically active material ina continuous fashion.

In some cases, the total combined amount of biologically active materialand grinding matrix in the mill at any given time is equal to or greaterthan a mass selected from the group consisting of: 200 grams, 500 grams,1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg, 75 kg, 100 kg, 150 kg, and200 kg.

Preferably, the total combined amount of biologically active materialand grinding matrix is less than 2000 kg.

In some embodiments the millable grinding matrix is selected from thegroup consisting of: mannitol, sorbitol, Isomalt, xylitol, maltitol,lactitol, erythritol, arabitol, ribitol, glucose, fructose, mannose,galactose, anhydrous lactose, lactose monohydrate, sucrose, maltose,trehalose, maltodextrins, dextrin, Inulin, dextrates, polydextrose,starch, wheat flour, corn flour, rice flour, rice starch, tapioca flour,tapioca starch, potato flour, potato starch, other flours and starches,milk powder, skim milk powders, other milk solids and dreviatives, soyflour, soy meal or other soy products, cellulose, microcystallinecellulose, microcystalline cellulose based co-blended materials,pregelatinized (or partially) starch, HPMC, CMC, HPC, citric acid,tartaric acid, malic acid, maleic acid fumaric acid, ascorbic acid,succinic acid, sodium citrate, sodium tartrate, sodium malate, sodiumascorbate, potassium citrate, potassium tartrate, potassium malate,sodium acetate, potassium ascorbate, sodium carbonate, potassiumcarbonate, magnesium carbonate, sodium bicarbonate, potassiumbicarbonate, calcium carbonate, dibasic calcium phosphate, tribasiccalcium phosphate, sodium sulfate, sodium chloride, sodiummetabisulphite, sodium thiosulfate, ammonium chloride, glauber's salt,ammonium carbonate, sodium bisulfate, magnesium sulfate, potash alum,potassium chloride, sodium hydrogen sulfate, sodium hydroxide,crystalline hydroxides, hydrogen carbonates, ammonium chloride,methylamine hydrochloride, ammonium bromide, silica, thermal silica,alumina, titanium dioxide, talc, chalk, mica, kaolin, bentonite,hectorite, magnesium trisilicate, clay based materials or aluminiumsilicates, sodium lauryl sulfate, sodium stearyl sulfate, sodium cetylsulfate, sodium cetostearyl sulfate, sodium docusate, sodiumdeoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate,glycerol distearate glyceryl palmitostearate, glyceryl behenate,glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC,Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide,benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188,poloxamer 338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether,polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil,polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil,polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil,polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitantrioleate, sucrose palmitate, sucrose stearate, sucrose distearate,sucrose laurate, glycocholic acid, sodium glycholate, cholic acid,soidum cholate, sodium deoxycholate, deoxycholic acid, sodiumtaurocholate, taurocholic acid, sodium taurodeoxycholate,taurodeoxycholic acid, soy lecithin, phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalenesulfonate condensate/Lignosulfonate blend, calcium dodecylbenzenesulfonate, sodium dodecylbenzene sulfonate, diisopropylnaphthaenesulphonate, erythritol distearate, naphthalene sulfonateformaldehyde condensate, nonylphenol ethoxylate (poe-30),tristyrylphenol ethoxylate, polyoxyethylene (15) tallowalkylamines,sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonatecondensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalenesulfonate, sodium methyl naphthalene formaldehyde sulfonate, sodiumn-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18),triethanolamine isodecanol phosphate ester, triethanolaminetristyrylphosphate ester, tristyrylphenol ethoxylate sulfate,bis(2-hydroxyethyl)tallowalkylamines or mixtures thereof. Preferably,the concentration of millable grinding matrix (or the total amount ofthe two or more millable grinding matrices) is selected from the groupconsisting of: 5-99% w/w, 10-95% w/w, 15-85% w/w, of 20-80% w/w, 25-75%w/w, 30-60% w/w, 40-50% w/w. Preferably, the concentration of thefacilitating agent is selected from 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5%w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w,0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.

In some embodiments, the faciliting agent is selected from the groupconsisting of: sodium lauryl sulfate, sodium stearyl sulfate, sodiumcetyl sulfate, sodium cetostearyl sulfate, sodium docusate, sodiumdeoxycholate, N-lauroylsarcosine sodium salt, glyceryl monostearate,glycerol distearate glyceryl palmitostearate, glyceryl behenate,glyceryl caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC,Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide,benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer 188,poloxamer 338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl ether,polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil,polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor oil,polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl60 hydrogenated castor oil, polyoxyl 100 hydrogenated castor oil,polyoxyl 200 hydrogenated castor oil, cetostearyl alcohol, macrogel 15hydroxystearate, sorbitan monopalmitate, sorbitan monostearate, sorbitantrioleate, Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate,Sucrose laurate, Glycocholic acid, sodium Glycholate, Cholic Acid,Soidum Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodiumtaurocholate, taurocholic acid, Sodium taurodeoxycholate,taurodeoxycholic acid, soy lecithin, phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalenesulfonate condensate/Lignosulfonate blend, Calcium DodecylbenzeneSulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropylnaphthaenesulphonate, erythritol distearate, Naphthalene SulfonateFormaldehyde Condensate, nonylphenol ethoxylate (poe-30),Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines,sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene sulfonatecondensate, sodium alkylbenzene sulfonate, sodium isopropyl naphthalenesulfonate, Sodium Methyl Naphthalene Formaldehyde Sulfonate, sodiumn-butyl naphthalene sulfonate, tridecyl alcohol ethoxylate (poe-18),Triethanolamine isodecanol phosphate ester, Triethanolaminetristyrylphosphate ester, Tristyrylphenol Ethoxylate Sulfate,Bis(2-hydroxyethyl)tallowalkylamines.

In other embodiments: meloxicam is milled with lactose monohydrate andalkyl sulfates; meloxicam is milled with lactose monohydrate and sodiumlauryl sulphate; meloxicam is milled with lactose monohydrate and sodiumoctadecyl sulphate; Meloxicam is milled with lactose monohydrate, alkylsulfates and another surfactant or polymers; meloxicam is milled withlactose monohydrate, sodium lauryl sulfate and polyether sulfates;meloxicam is milled with lactose monohydrate, sodium lauryl sulfate andpolyethylene glycol 40 stearate; meloxicam is milled with lactosemonohydrate, sodium lauryl sulfate and polyethylene glycol 100 stearate;meloxicam is milled with lactose monohydrate, sodium lauryl sulfate anda poloxamer; meloxicam is milled with lactose monohydrate, sodium laurylsulfate and poloxamer 407; meloxicam is milled with lactose monohydrate,sodium lauryl sulfate and poloxamer 338; meloxicam is milled withlactose monohydrate, sodium lauryl sulfate and poloxamer 188; meloxicamis milled with lactose monohydrate, sodium lauryl sulfate and a solidpolyethylene glycol; meloxicam is milled with lactose monohydrate,sodium lauryl sulfate and polyethylene glycol 6000; meloxicam is milledwith lactose monohydrate, sodium lauryl sulfate and polyethylene glycol3000; meloxicam is milled with lactose monohydrate and polyethersulfates; meloxicam is milled with lactose monohydrate and polyethyleneglycol 40 stearate; meloxicam is milled with lactose monohydrate andpolyethylene glycol 100 stearate meloxicam is milled with lactosemonohydrate and polyvinyl-pyrrolidine; meloxicam is milled with lactosemonohydrate and polyvinyl-pyrrolidone with an approximate molecularweight of 30,000-40,000; meloxicam is milled with lactose monohydrateand alkyl sulfonates; meloxicam is milled with lactose monohydrate anddocusate sodium; meloxicam is milled with lactose monohydrate and asurfactant; meloxicam is milled with lactose monohydrate and lecithin;meloxicam is milled with lactose monohydrate and sodium n-lauroylsarcosine; meloxicam is milled with lactose monohydrate andpolyoxyethylene alkyl ether surfactants; meloxicam is milled withlactose monohydrate and PEG 6000. In another preferred formulationmeloxicam is milled with lactose monohydrate and silica; meloxicam ismilled with lactose monohydrate and Aerosil R972 fumed silica; meloxicamis milled with with lactose monohydrate, tartaric acid and sodium laurylsulfate; meloxicam is milled with with lactose monohydrate, sodiumbicarbonate and sodium lauryl sulfate; meloxicam is milled with lactosemonohydrate, potassium bicarbonate and sodium lauryl sulfate. In anotherpreferred embodiment, meloxicam is milled with mannitol and alkylsulfates; meloxicam is milled with mannitol and sodium lauryl sulfate;meloxicam is milled with mannitol and sodium octadecyl sulfate;Meloxicam is milled with mannitol, alkyl sulfates and another surfactantor polymers; meloxicam is milled with mannitol, sodium lauryl sulfateand polyether sulfates; meloxicam is milled with mannitol, sodium laurylsulfate and polyethylene glycol 40 stearate; meloxicam is milled withmannitol, sodium lauryl sulfate and polyethylene glycol 100 stearate;meloxicam is milled with mannitol, sodium lauryl sulfate and apoloxamer; meloxicam is milled with mannitol, sodium lauryl sulfate andpoloxamer 407; meloxicam is milled with mannitol, sodium lauryl sulfateand poloxamer 338; meloxicam is milled with mannitol, sodium laurylsulfate and poloxamer 188; meloxicam is milled with mannitol, sodiumlauryl sulfate and a solid polyethylene glycol; meloxicam is milled withmannitol, sodium lauryl sulfate and polyethylene glycol 6000; meloxicamis milled with mannitol, sodium lauryl sulfate and polyethylene glycol3000; Meloxicam is milled with mannitol and polyether sulfates;meloxicam is milled with mannitol and polyethylene glycol 40 stearate;meloxicam is milled with mannitol and polyethylene glycol 100 stearateIn another preferred embodiment meloxicam is milled with mannitol andpolyvinyl-pyrrolidine; meloxicam is milled with mannitol andpolyvinyl-pyrrolidone with an approximate molecular weight of30,000-40,000; meloxicam is milled with mannitol and alkyl sulfonates;meloxicam is milled with mannitol and docusate sodium; meloxicam ismilled with mannitol and a surfactant; meloxicam is milled with mannitoland lecithin; meloxicam is milled with mannitol and sodium n-lauroylsarcosine; meloxicam is milled with mannitol and polyoxyethylene alkylether surfactants; meloxicam is milled with mannitol and PEG 6000. Inanother preferred formulation meloxicam is milled with mannitol andsilica; meloxicam is milled with mannitol and Aerosil R972 fumed silica;meloxicam is milled with with mannitol, tartaric acid and sodium laurylsulfate; meloxicam is milled with with mannitol, sodium bicarbonate andsodium lauryl sulfate; and meloxicam is milled with mannitol, potassiumbicarbonate and sodium lauryl sulfate.

Those skilled in the art will appreciate that the disclosure describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the disclosureincludes all such variations and modifications. The disclosure alsoincludes all of the steps, features, compositions and materials referredto or indicated in the specification, individually or collectively andany and all combinations or any two or more of the steps or features.

The present disclosure is not to be limited in scope by the specificembodiments described herein, which are intended for the purpose ofexemplification only. Functionally equivalent products, compositions andmethods are clearly within the scope of the disclosure as describedherein.

The disclosure described herein may include one or more ranges of values(e.g. size, concentration etc). A range of values will be understood toinclude all values within the range, including the values defining therange, and values adjacent to the range that lead to the same orsubstantially the same outcome as the values immediately adjacent tothat value which defines the boundary to the range.

The entire disclosures of all publications (including patents, patentapplications, journal articles, laboratory manuals, books, or otherdocuments) cited herein are hereby incorporated by reference. Inclusiondoes not constitute an admission is made that any of the referencesconstitute prior art or are part of the common general knowledge ofthose working in the field to which this disclosure relates.

Throughout this specification, unless the context requires otherwise,the word “comprise” or variations, such as “comprises” or “comprising”will be understood to imply the inclusion of a stated integer, or groupof integers, but not the exclusion of any other integers or group ofintegers. It is also noted that in this disclosure, and particularly inthe claims and/or paragraphs, terms such as “comprises”, “comprised”,“comprising” and the like can have the meaning attributed to it in USPatent law; e.g., they can mean “includes”, “included”, “including”, andthe like.

“Therapeutically effective amount” as used herein with respect tomethods of treatment and in particular drug dosage, shall mean thatdosage that provides the specific pharmacological response for which thedrug is administered in a significant number of subjects in need of suchtreatment. It is emphasized that “therapeutically effective amount,”administered to a particular subject in a particular instance will notalways be effective in treating the diseases described herein, eventhough such dosage is deemed a “therapeutically effective amount” bythose skilled in the art. It is to be further understood that drugdosages are, in particular instances, measured as oral dosages, or withreference to drug levels as measured in blood.

The term “inhibit” is defined to include its generally accepted meaningwhich includes prohibiting, preventing, restraining, and lowering,stopping, or reversing progression or severity, and such action on aresultant symptom. As such the present disclosure includes both medicaltherapeutic and prophylactic administration, as appropriate.

Particle Size

There is a wide range of techniques that can be utilized to characterizethe particle size of a material. Those skilled in the art alsounderstand that almost all these techniques do not physically measurethe actually particle size, as one might measure something with a ruler,but measure a physical phenomenon which is interpreted to indicate aparticle size.

For measurements made using a laser diffraction instrument, or anequivalent method known in the art, the term “median particle size” isdefined as the median particle diameter as determined on an equivalentspherical particle volume basis. Where the term median is used, it isunderstood to describe the particle size that divides the population inhalf such that 50% of the population is greater than or less than thissize. The median particle size is often written as D50, D(0.50) orD[0.5] or similar. As used herein D50, D(0.50) or D[0.5] or similarshall be taken to mean ‘median particle size’.

The term “Dx of the particle size distribution” refers to the xthpercentile of the distribution; thus, D90 refers to the 90^(th)percentile, D95 refers to the 95^(th) percentile, and so forth. TakingD90 as an example this can often be written as, D(0.90) or D[0.9] orsimilar. With respect to the median particle size and Dx an upper case Dor lowercase d are interchangeable and have the same meaning. Anothercommonly used way of describing a particle size distribution measured bylaser diffraction, or an equivalent method known in the art, is todescribe what % of a distribution is under or over a nominated size. Theterm “percentage less than” also written as “%<” is defined as thepercentage, by volume, of a particle size distribution under a nominatedsize—for example the % <1000 nm. The term “percentage greater than” alsowritten as “%>” is defined as the percentage, by volume, of a particlesize distribution over a nominated size—for example the %>1000 nm.

For many of the materials subject to the methods of this disclosure theparticle size can be easily measured. Where the active material has poorwater solubility and the matrix it is milled in has good watersolubility the powder can simply be dispersed in an aqueous solvent. Inthis scenario the matrix dissolves leaving the active material dispersedin the solvent. This suspension can then be measured by techniques suchas photon correlation spectroscopy or laser diffraction.

Suitable methods to measure an accurate particle size where the matrixhas low solubility in a water-based dispersant are outlined below.

-   -   1. In the circumstance where an insoluble matrix such as        microcrystalline cellulose prevents the measurement of the        active material separation techniques such as filtration or        centrifugation could be used to separate the insoluble matrix        from the active material particles. Other ancillary techniques        would also be required to determine if any active material was        removed by the separation technique so that this could be taken        into account.    -   2. In some circumstances image analysis could be used to obtain        information about the particle size distribution of the active        material. Suitable image measurement techniques might include        transmission electron microscopy (TEM), scanning electron        microscopy (SEM), optical microscopy and confocal microscopy. In        addition to these standard techniques some additional technique        would be required to be used in parallel to differentiate the        active material and matrix particles. Depending on the chemical        makeup of the materials involved possible techniques could be        elemental analysis, Raman spectroscopy, FTIR spectroscopy or        fluorescence spectroscopy.

Throughout this specification, unless the context requires otherwise,the phrase “dry mill” or variations, such as “dry milling”, should beunderstood to refer to milling in at least the substantial absence ofliquids. If liquids are present, they are present in such amounts thatthe contents of the mill retain the characteristics of a dry powder.

The term “millable” means that a material is capable of being reduced inparticle under the dry milling conditions used. In some cases, themilled grinding matrix is of a comparable particle size to thebiologically active material. In other cases the particle size of thematrix is substantially reduced by milling but the resulting particlesize is larger than the milled biologically active material.

Grinding Matrix

As will be described subsequently, selection of an appropriate grindingmatrix affords particular advantageous applications of the method of thepresent disclosure. Again, as will be described subsequently, a highlyadvantageous aspect of the present disclosure is that certain grindingmatrixes appropriate for use in the method of the disclosure are alsoappropriate for use in a medicament. The present disclosure encompassesmethods for the production of a medicament incorporating both meloxicamand the grinding matrix or in some cases the abiraterone acetate and aportion of the grinding matrix, medicaments so produced, and methods oftreatment using the medicament. The medicament may include only themilled abiraterone acetate together with the milled grinding matrix or,more preferably, the milled meloxicam and milled grinding matrix may becombined with one or more pharmaceutically acceptable carriers, as wellas any desired excipients or other like agents commonly used in thepreparation of medicaments.

In some cases at least one component of the grinding matrix is harderthan the meloxicam, and is thus capable of reducing the particle size ofthe meloxicam under the dry milling conditions of the disclosure. Againwithout wishing to be bound by theory, under these circumstances it isbelieved that the millable grinding matrix affords the advantage of thepresent disclosure through a second route, with the smaller particles ofgrinding matrix produced under the dry milling conditions enablinggreater interaction with the meloxicam.

The quantity of the grinding matrix relative to the quantity ofmeloxicam, and the extent of size reduction of the grinding matrix, issufficient to inhibit re-agglomeration of the particles of the activematerial. In some embodiments, the quantity of the grinding matrixrelative to the quantity of meloxicam, and the extent of size reductionof the grinding matrix, is sufficient to inhibit re-agglomeration of theparticles of the active material.

In some embodiments, the grinding matrix has a low tendency toagglomerate during dry milling. While it is difficult to objectivelyquantify the tendency to agglomerate during milling, it is possible toobtain a subjective measure by observing the level of “caking” of thegrinding matrix in the milling chamber of the mill as dry millingprogresses.

The grinding matrix may be an inorganic or organic substance.

Milling Bodies

In the method of the present disclosure, where milling bodies areutilized, the milling bodies are preferably chemically inert and rigid.The term “chemically-inert”, as used herein, means that the millingbodies do not react chemically with the meloxicam or the grindingmatrix.

As described above, the milling bodies are essentially resistant tofracture and erosion in the milling process.

The milling bodies are desirably provided in the form of bodies whichmay have any of a variety of smooth, regular shapes, flat or curvedsurfaces, and lacking sharp or raised edges. For example, suitablemilling bodies can be in the form of bodies having ellipsoidal, ovoid,spherical or right cylindrical shapes. In some embodiments, the millingbodies are provided in the form of one or more of beads, balls, spheres,rods, right cylinders, drums or radius-end right cylinders (i.e., rightcylinders having hemispherical bases with the same radius as thecylinder).

Depending on the nature of the meloxicam and the grinding matrix, themilling bodies desirably have an effective mean diameter between about0.1 and 30 mm, more preferably between about 1 and about 15 mm, stillmore preferably between about 3 and 10 mm.

The milling bodies may comprise various substances such as ceramic,glass, metal or polymeric compositions, in a particulate form. Suitablemetal milling bodies are typically spherical and generally have goodhardness (i.e. RHC 60-70), roundness, high wear resistance, and narrowsize distribution and can include, for example, balls fabricated fromtype 52100 chrome steel, type 304, 316 or 440C stainless steel or type1065 high carbon steel.

Ceramics, for example, can be selected from a wide array of ceramicsdesirably having sufficient hardness and resistance to fracture toenable them to avoid being chipped or crushed during milling and alsohaving sufficiently high density. Suitable densities for milling bodiescan range from about 1 to 15 g/cm³, preferably from about 1 to 8 g/cm³.Ceramics can be selected from steatite, aluminum oxide, zirconium oxide,zirconia-silica, yttria-stabilized zirconium oxide, magnesia-stabilizedzirconium oxide, silicon nitride, silicon carbide, cobalt-stabilizedtungsten carbide, and the like, as well as mixtures thereof.

Glass milling bodies are spherical (e.g. beads), have a narrow sizedistribution, are durable, and include, for example, lead-free soda limeglass and borosilicate glass. Polymeric milling bodies are preferablysubstantially spherical and can be selected from a wide array ofpolymeric resins having sufficient hardness and friability to enablethem to avoid being chipped or crushed during milling,abrasion-resistance to minimize attrition resulting in contamination ofthe product, and freedom from impurities such as metals, solvents, andresidual monomers.

Milling bodies can be formed from polymeric resins. Polymeric resins,for example, can be selected from crosslinked polystyrenes, such aspolystyrene crosslinked with divinylbenzene, styrene copolymers,polyacrylates such as polymethylmethacrylate, polycarbonates,polyacetals, vinyl chloride polymers and copolymers, polyurethanes,polyamides, high density polyethylenes, polypropylenes, and the like.The use of polymeric milling bodies to grind materials down to a verysmall particle size (as opposed to mechanochemical synthesis) isdisclosed, for example, in U.S. Pat. Nos. 5,478,705 and 5,500,331.Polymeric resins typically can have densities ranging from about 0.8 to3.0 g/cm³. Higher density polymeric resins are generally preferred.Alternatively, the milling bodies can be composite bodies comprisingdense core bodies having a polymeric resin adhered thereon. Coreparticles can be selected from substances known to be useful as millingbodies, for example, glass, alumina, zirconia silica, zirconium oxide,stainless steel, and the like. Core substances have densities greaterthan about 2.5 g/cm³.

In one embodiment of the disclosure, the milling bodies are formed froma ferromagnetic substance, thereby facilitating removal of contaminantsarising from wear of the milling bodies by the use of magneticseparation techniques.

Each type of milling body has its own advantages. For example, metalshave the highest specific gravities, which increase grinding efficiencydue to increased impact energy. Metal costs range from low to high, butmetal contamination of final product can be an issue. Glasses areadvantageous from the standpoint of low cost and the availability ofsmall bead sizes as low as 0.004 mm. However, the specific gravity ofglasses is lower than other bodies and significantly more milling timeis required. Finally, ceramics are advantageous from the standpoint oflow wear and contamination, ease of cleaning, and high hardness.

Dry Milling

In the dry milling process of the present disclosure, the meloxicam andgrinding matrix, in the form of crystals, powders, or the like, arecombined in suitable proportions with or without a plurality of millingbodies in a milling chamber that is mechanically agitated for apredetermined period of time at a predetermined intensity of agitation.Typically, a milling apparatus is used to impart motion to contents ofthe mill including any milling bodies by the external application ofagitation, a stream of dry gas or other force, whereby varioustranslational, rotational or inversion motions or combinations thereofare applied to the milling chamber and its contents, or by the internalapplication of agitation through a rotating shaft terminating in ablade, propeller, impeller or paddle or by a combination of bothactions.

During milling, motion imparted to the milling bodies or gas flowingthrough the milling system can result in application of shearing forcesas well as multiple impacts or collisions having significant intensitybetween the mill components, any milling bodies utilized and theparticles of meloxicam and the grinding matrix. The nature and intensityof the forces applied by the milling bodies to the meloxicam and thegrinding matrix is influenced by a wide variety of processing parametersincluding: the type of milling apparatus; the intensity of the forcesgenerated, the kinematic aspects of the process; the size, density,shape, and composition of any milling bodies used; the weight ratio ofthe meloxicam and grinding matrix mixture to the milling bodies; theduration of milling; the physical properties of both the meloxicam andthe grinding matrix; the atmosphere present during milling; and others.

Advantageously, the mill is capable of repeatedly or continuouslyapplying mechanical compressive forces and shear stress to the meloxicamand the grinding matrix. Throughout the remainder of the specificationreference will be made to dry milling being carried out by way of a ballmill. Examples of this type of mill are attritor mills, nutating mills,tower mills, planetary mills, vibratory mills, gravity-dependent-typeball mills, rod mills, roller mills or crusher mills, and pulverizingmills. It will be appreciated that dry milling in accordance with themethod of the disclosure may also be achieved by any suitable millingmethod or means.

In some cases, the particle size of the meloxicam prior to dry millingaccording to the methods described herein is less than about 1000 μm, asdetermined by sieve analysis. If the particle size of the meloxicam isgreater than about 1000 μm, then it is preferred that the particles ofthe meloxicam substrate be reduced in size to less than 1000 μm usinganother particle size reduction method prior to dry milling according tothe methods described herein.

Agglomerates of Meloxicam after Processing

Agglomerates comprising particles of meloxicam having a particle sizewithin the ranges specified herein, should be understood to fall withinthe scope of the present disclosure, regardless of whether theagglomerates exceed the ranges specified above.

Processing Time

In some embodiments, the meloxicam and the grinding matrix are drymilled for the shortest time necessary to minimize any possiblecontamination from the mill process and/or any milling bodies utilized.This time varies greatly, depending on the meloxicam and the grindingmatrix, and may range from as short as 1 minute to several hours.

Suitable rates of agitation and total milling times are adjusted for thetype and size of milling apparatus, the type and size of any millingmedia utilized, the weight ratio of the meloxicam and grinding matrixmixture to the plurality of milling bodies that may be utilized, thechemical and physical properties of the meloxicam and grinding matrix,and other parameters that may be optimized empirically.

In some embodiments, the grinding matrix (the materials milled togetherwith meloxicam) is not separated from the meloxicam but is maintainedwith the meloxicam in the final product. In some embodiments thegrinding matrix is considered to be Generally Regarded as Safe (GRAS)for pharmaceutical products.

In an alternative aspect, the grinding matrix is separated from themeloxicam. In one aspect, where the grinding matrix is not fully milled,the unmilled grinding matrix is separated from the meloxicam. In afurther aspect, at least a portion of the milled grinding matrix isseparated from the meloxicam.

Any portion of the grinding matrix may be removed, including but notlimited to 10%, 25%, 50%, 75%, or substantially all of the grindingmatrix.

In some embodiments of the disclosure, a significant portion of themilled grinding matrix may comprise particles of a size similar toand/or smaller than the particles comprising the meloxicam. Where theportion of the milled grinding matrix to be separated from the particlescomprising the meloxicam comprises particles of a size similar to and/orsmaller than the particles comprising the meloxicam, separationtechniques based on size distribution are inapplicable. In thesecircumstances, the method of the present disclosure may involveseparation of at least a portion of the milled grinding matrix from themeloxicam by techniques including, but not limited to, electrostaticseparation, magnetic separation, centrifugation (density separation),hydrodynamic separation, and froth flotation. Advantageously, the stepof removing at least a portion of the milled grinding matrix from themeloxicam may be performed through means such as selective dissolution,washing, or sublimation.

An advantageous aspect of the disclosure would be the use of grindingmatrix that has two or more components where at least one component iswater soluble and at least one component has low solubility in water. Inthis case washing can be used to remove the matrix component soluble inwater leaving the meloxicam dispersed in the remaining matrixcomponents. In a highly advantageous aspect of the disclosure the matrixwith low solubility is a functional excipient.

A highly advantageous aspect of the present disclosure is that certaingrinding matrixes appropriate for use in the method of the disclosureare also pharmaceutically acceptable and thus appropriate for use in amedicament. Where the method of the present disclosure does not involvecomplete separation of the grinding matrix from the meloxicam, thepresent disclosure encompasses methods for the production of amedicament incorporating both the meloxicam and at least a portion ofthe milled grinding matrix, medicaments so produced and methods oftreatment of an animal, including man, using a therapeutically effectiveamount of said meloxicam by way of said medicaments.

Dosage Forms

The dosage forms of the present disclosure may include meloxicam,optionally together with the grinding matrix or at least a portion ofthe grinding matrix, with or without milling aids, facilitating agents,combined with one or more pharmaceutically acceptable carriers, as wellas other agents commonly used in the preparation of pharmaceuticallyacceptable compositions.

As used herein “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like that arephysiologically compatible. Preferably, the carrier is suitable forparenteral administration, intravenous, intraperitoneal, intramuscular,sublingual, pulmonary, transdermal or oral administration.Pharmaceutically acceptable carriers include sterile aqueous solutionsor dispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersion. The use of such media andagents for the manufacture of medicaments is well known in the art.Except insofar as any conventional media or agent is incompatible withthe pharmaceutically acceptable material, use thereof in the manufactureof a pharmaceutical composition according to the disclosure iscontemplated.

Pharmaceutically acceptable carriers according to the disclosure mayinclude one or more of the following examples:

-   -   (1) surfactants and polymers including, but not limited to        polyethylene glycol (PEG), polyvinylpyrrolidone (PVP),        polyvinylalcohol, crospovidone,        polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose        derivatives, hydroxypropylmethyl cellulose, hydroxypropyl        cellulose, carboxymethylethyl cellulose, hydroxypropyllmethyl        cellulose phthalate, polyacrylates and polymethacrylates, urea,        sugars, polyols, and their polymers, emulsifiers, sugar gum,        starch, organic acids and their salts, vinyl pyrrolidone and        vinyl acetate    -   (2) binding agents such as various celluloses and cross-linked        polyvinylpyrrolidone, microcrystalline cellulose; and or    -   (3) filling agents such as lactose monohydrate, lactose        anhydrous, microcrystalline cellulose and various starches; and        or    -   (4) lubricating agents such as agents that act on the        flowability of the powder to be compressed, including colloidal        silicon dioxide, talc, stearic acid, magnesium stearate, calcium        stearate, silica gel; and or    -   (5) sweeteners such as any natural or artificial sweetener        including sucrose, xylitol, sodium saccharin, cyclamate,        aspartame, and accsulfame K; and or    -   (6) flavouring agents; and or    -   (7) preservatives such as potassium sorbate, methylparaben,        propylparaben, benzoic acid and its salts, other esters of        parahydroxybenzoic acid such as butylparaben, alcohols such as        ethyl or benzyl alcohol, phenolic chemicals such as phenol, or        quarternary compounds such as benzalkonium chloride; and or    -   (8) buffers; and or    -   (9) Diluents such as pharmaceutically acceptable inert fillers,        such as microcrystalline cellulose, lactose, dibasic calcium        phosphate, saccharides, and/or mixtures of any of the foregoing;        and or    -   (10) wetting agents such as corn starch, potato starch, maize        starch, and modified starches, croscarmellose sodium,        crosspovidone, sodium starch glycolate, and mixtures thereof;        and or    -   (11) disintegrants; and or    -   (12) effervescent agents such as effervescent couples such as an        organic acid (e.g., citric, tartaric, malic, fumaric, adipic,        succinic, and alginic acids and anhydrides and acid salts), or a        carbonate (e.g. sodium carbonate, potassium carbonate, magnesium        carbonate, sodium glycine carbonate, L-lysine carbonate, and        arginine carbonate) or bicarbonate (e.g. sodium bicarbonate or        potassium bicarbonate); and or    -   (13) other pharmaceutically acceptable excipients.

EXAMPLES

The following Examples are provided for illustrative purposes only, andare not intended to limit the scope of the processes or compositions ofthe disclosure.

Example 1: Production of Attrited Blends Containing Meloxicam

Meloxicam was dry milled in a mill with milling bodies in the presenceof lactose monohydrate and sodium lauryl sulfate to produced attritedblends. In the attrited blends the particle size of the meloxicam isreduced compared to the starting material. Among the attrited blendsproduced in this manner were the two described below in Table 1.

TABLE 1 Composition of Two Attrited Blends Component Attrited Blend 1 (%w/w) Attrited Blend 2 (% w/w) Meloxicam 18.00 7.14 Lactose 74.44 89.86monohydrate Sodium lauryl 7.56 3.00 sulfate

The particle size distribution (PSD) of material in attrited blends canbe determined using a Malvern Mastersizer 2000 fitted with a MalvernHydro 2000S pump unit. Measurement settings can be: Measurement Time: 12seconds, Measurement cycles: 3. Final result generated by averaging the3 measurements. Samples can prepared by adding 200 mg of milled materialto 5.0 mL of 1% PVP in 10 mM hydrochloric acid (HCl), vortexing for 1min and then sonicating. From this suspension enough is added into thedispersant (10 mM HCl) to attain a desired obscuration level. Ifnecessary an extra 1-2 minutes of sonication is applied using theinternal sonication probe in the measurement cell. The refractive indexof the active ingredient to be measured was in the range of 1.49-1.73.The particle size of meloxicam in two different attrited blends, bothprepared in a manner similar to that used to prepare the attrited blendsdescribed above, was measured essentially as described above. Thefollowing values were obtained:

Attrited Blend A

Specific Surface Area: 31.8 m²/g

Surface Weighted Mean D[3,2]: 0.189 μm

Volume Weighted Mean D[4,3]: 0.707 μm

D(10) or D(0.1): 0.082 μm

D(50) or D(0.5): 0.260 μm

D(90) or D(0.5): 1.945

D(98) or D(0.98): 3.553 μm

Attrited Blend B

Specific Surface Area: 33 m²/g

Surface Weighted Mean D[3,2]: 0.182 μm

Volume Weighted Mean D[4,3]: 0.638 μm

D(10) or D(0.1): 0.081 μm

D(50) or D(0.5): 0.242 μm

D(90) or D(0.5): 1.768 μm

D(98) or D(0.98): 3.327 μm

Example 2: Preparation of Dosage Forms

The Attrited Blends were combined with intragranular excipients(microcrystalline cellulose, croscarmellose sodium, and sodium laurylsulfate) and roller compacted into ribbons. The ribbons were milled intogranules and blended with extragranular excipients (croscarmellosesodium, sodium lauryl sulfate, and sodium stearyl fumarate) to produce aFinal Blend suitable for high speed automated encapsulation. The FinalBlend was encapsulated to produce compositions containing 5 mg or 10 mgof meloxicam. The components of the Final Blend are as shown below inTable 2.

TABLE 2 Components of Final Blend for Preparation of Capsules FinalBlend Components (% w/w) Meloxicam 4.00 Lactose monohydrate 16.54 Sodiumlauryl sulfate 1.68 Microcrystalline cellulose-intragranular 69.78Croscarmellose sodium-intragranular 3.00 Sodium laurylsulfate-intragranular 0.50 Sodium stearyl fumarate-intragranular 1.00Croscarmellose sodium-extragranular 3.00 Sodium laurylsulfate-extragranular 0.50 Total 100.0

The dissolution rate of meloxicam 5 mg and 10 mg capsules was analyzed.For the 5 mg capsules, the dissolution conditions were: USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 500 mL of pH 6.1 phosphatebuffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5° C. For the10 mg capsules, the dissolution conditions were: USP Apparatus 1(baskets) set to rotation speed of 100 RPM in 1000 mL of pH 6.1phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.±0.5° C.For the 5 mg capsules, at least 90% of the meloxicam dissolved within 5minutes. For the 10 mg capsules, at least 90% of the meloxicam dissolvedwithin 10 minutes.

Example 3: Pharmacokinetic Testing

A human clinical trial was used to obtain pharmacokinetic data for themeloxicam 5 mg and 10 mg meloxicam capsules described above. Also testedwas Mobic® 15 mg tablets. The results are presented in Table 3.

TABLE 3 Summary of Plasma Pharmacokinetic Parameters Mean ± SD (N)Meloxicam Capsules Meloxicam Capsules Meloxicam Parameter 10 mg 10 mgCapsules 5 mg Mobic 15 mg Tablet (unit) (Fasted) (Fed) (Fasted) (Fasted)C_(max) 1252.78 ± 254.22  973.88 ± 165.36 642.39 ± 138.49 1288.81 ±424.40  (ng/mL) (27) (26) (26) (27) t_(max)* (h) 2.00 (1.00, 5.00) 5.00(1.50, 16.02) 2.00 (0.50, 4.07) 4.00 (2.02, 8.00) (27) (26) (26) (27)AUC_(0−t) 28190.52 ± 9264.72  26681.19 ± 9748.03  14206.47 ± 5415.31 39093.82 ± 16500.17 (ng*h/mL) (27) (26) (26) (27) AUC_(0−∞) 29173.01 ±11042.09 27145.85 ± 11469.51 13610.54 ± 3342.69  40875.58 ± 11733.47(ng*h/mL) (26) (24) (24) (23) t_(1/2) (h) 22.04 ± 10.08 22.27 ± 9.88 22.32 ± 10.91 23.64 ± 10.04 (27) (26) (26) (27) N = number of subjectsrandomized *t_(max) is presented as median (min, max)

Example 4: Clinical Testing in Patients Suffering Osteoarthritis(OA)-Related Pain

A Phase 3, multicenter, randomized, double-blind, double-dummy,placebo-controlled, fixed-dose, parallel-group trial that included 403subjects with clinical and radiologic evidence of osteoarthritis(OA)-related pain that required NSAID or acetaminophen treatment.

The subject population was representative of patients with active OArequiring acetaminophen or NSAID treatment—the mean age overall was 60.7years, and subjects were generally overweight (mean BMI, 30.94 kg/m²).

Assessments of OA-associated pain and measures of function and stiffnessutilized the WOMAC scale, a standard instrument that has been widelyused to evaluate the utility of pharmacologic and non-pharmacologicinterventions for the treatment of OA. Additional measures included painintensity assessed by an 11-point numerical pain scale prior to and 2hours after dosing and patient and clinical global impressions of changeat Week 12.

WOMAC pain subscale scores at Baseline prior to randomization were high,indicative of a high degree of OA pain in the trial subjects, and weresimilar across treatment groups; the mean overall score (72.64 mm) wasnearly twice the required minimum score for trial entry (40 mm).

Efficacy of Meloxicam Capsules 5 mg and 10 mg prepared as describedherein was demonstrated by a combination of clinically meaningful andstatistically significant results in the primary, secondary, and posthoc analyses. The primary efficacy parameter, change from Baseline toWeek 12 in the WOMAC pain subscale score (MMRM analysis), demonstrated astatistically significant treatment benefit for once daily MeloxicamCapsules at both 5 mg (P=0.0005) and 10 mg (P=0.0059) dose levelscompared with placebo.

Sensitivity analyses, which included more conservative requirements toestablish efficacy, demonstrated that the model used in this analysiswas robust and reliable. As a whole, although the limited numbers(resulting from low dropout rates) made it difficult to adequatelyassess the missing data mechanism, it was concluded that the primaryefficacy analyses were appropriate and that the missing at random (MAR)assumption required to use the MMRM model assumptions appear reasonable.

Sensitivity analyses assessing the effect of rescue medication usagewere also consistent with the primary efficacy analysis. The SilvermanIntegrated Rank Analysis, which takes into account rescue medication useand WOMAC pain subscale scores simultaneously, demonstrated astatistically significant difference in the LS mean change from Baselineto Week 12 for both the Meloxicam Capsules 5 mg (P<0.0001) and 10 mg(P<0.0001) groups compared with placebo.

Secondary efficacy analyses of WOMAC pain subscale scores confirmed theresults of the primary efficacy analysis. Treatment with MeloxicamCapsules 5 mg once daily resulted in significant changes from Baselinein WOMAC pain subscale scores at Weeks 2 (P=0.0003) and 6 (P=0.0004),and for the average of the 12-week trial period (P<0.0001), comparedwith placebo. Evidence of efficacy was also noted for the MeloxicamCapsules 10 mg treatment group at each trial visit; significantimprovements compared with placebo were observed for the change fromBaseline to Week 6 (P=0.0008) and to the average over the 12-week period(P=0.0024).

Similar to the results based on the WOMAC pain subscale, significantdifferences vs placebo in the LS mean change from Baseline in WOMACfunction subscale scores were achieved by the Meloxicam Capsules 5 mggroup at Week 2 (P=0.0001), Week 6 (P=0.0012), Week 12 (P=0.0014), andfor the average over the 12-week period (P<0.0001). Significantdifferences vs placebo were also noted for the Meloxicam Capsules 10 mgtreatment at Weeks 6 (P=0.0014), Week 12 (P=0.0014), and for the averageover the 12-week period (P=0.0018). Significant differences in WOMACstiffness subscale scores were achieved by both the Meloxicam Capsules 5mg and 10 mg groups for Weeks 2, 6, 12, and the average over the 12-weekperiod (5 mg: P≤0.0001, 10 mg: P≤0.0379). These results demonstrate thatboth dosing regimens of Meloxicam Capsules not only provide relief ofpain associated with OA, but also improve functional deficits andstiffness associated with OA.

The total WOMAC score provides a useful measure of improvement inoverall symptoms associated with OA, including function, stiffness, andpain. Subjects in the Meloxicam Capsules 5 mg and 10 mg treatment groupsachieved lower mean scores at each post-Baseline trial visit comparedwith the placebo group. Significant differences vs placebo in the LSmean change from Baseline in total WOMAC scores were achieved by theMeloxicam Capsules 5 mg group at each trial visit and over the 12-weekperiod (P≤0.0014). Significant differences vs placebo were also notedfor the Meloxicam Capsules 10 mg treatment group at Week 6, Week 12, andthe average over the 12-week trial period (P≤0.0020).

Significant numbers of subjects in the Meloxicam Capsules 5 mg groupwere considered responders to trial drug treatment based on minimaldifferences in WOMAC pain subscale scores (10 mm) from Baseline at Weeks2 and 6 and clinically meaningful (ie, ≥30% and ≥50%) reductions inWOMAC pain subscale scores from Baseline at Weeks 2, 6, and 12 followingthe start of dosing compared with placebo. A higher number of subjectsin the Meloxicam Capsules 5 mg group also achieved ≥10 mm reduction inWOMAC pain subscale scores from Baseline at Week 12. Significant numbersof subjects in the Meloxicam Capsules 10 mg group were consideredresponders at Weeks 6 (≥10 mm, ≥30%, ≥50% reductions in WOMAC painsubscale) and 12 (≥50% reduction in WOMAC pain subscale) compared withplacebo. Significantly more responders were noted in the MeloxicamCapsules 5 mg and 10 mg compared with placebo using modifiedOMERACT-OARSI criteria.

In the continuous responder analysis, based on WOMAC pain subscalescores, a higher percentage of subjects in the Meloxicam Capsules 5 mgand 10 mg groups experienced reductions in WOMAC pain subscale scoreswith a clear separation of the curves for Meloxicam Capsules 5 mg and 10mg treatment groups compared with placebo at each trial visit.

Patient-reported outcomes provide an important measure of the clinicalsignificance of observed treatment benefits from the subject'sperspective. More subjects in both the Meloxicam Capsules 5 mg treatmentgroup (50.0%) and 10 mg treatment group (52.8%) assessed their overallstatus as “very much improved” or “much improved” following treatmentwith trial drug. This is in contrast to only 40.0% of subjects in theplacebo group.

Physicians assessed the overall status of subjects as “very muchimproved” or “much improved” for the majority of subjects receivingMeloxicam Capsules: 51.1% of subjects in the Meloxicam Capsules 5 mgtreatment group and 52.8% of subjects in the Meloxicam Capsules 10 mgtreatment group. This is in contrast to the placebo group, where only38.5% of physicians rated subjects' overall status as “very muchimproved” or “much improved.” Assessments of “very much improved” and“much improved” indicate clinically significant treatment benefits andimprovements in overall symptoms associated with OA.

In secondary efficacy analyses, the patient global impression of change(PGIC) and the clinical global impression of change (CGIC) from Baselineto Week 12 were generally positive by both measures as indicated above.Meloxicam Capsules 5 mg and 10 mg both demonstrated significantdifferences compared with placebo in the overall response patterns forthe PGIC (P=0.0049 and P=0.0012, respectively) and the CGIC (P=0.0070and P=0.0013, respectively). These results indicate that subjects onboth dosing regimens derived an overall treatment benefit compared withplacebo as evidenced by favorable overall impressions of their change instatus at Week 12 compared with Baseline.

The LS mean daily rescue medication usage was lowest in the MeloxicamCapsules 10 mg treatment group (313.6 mg, P=0.0024 vs placebo). Subjectsin the Meloxicam Capsules 5 mg treatment group (LS mean 25.3 days,P=0.0007 vs placebo) and Meloxicam Capsules 10 mg treatment group (LSmean 23.5 days, P<0.0001 vs placebo) demonstrated fewer average numberof days of rescue medication usage compared with the placebo group (LSmean 33.9 days).

Post hoc analyses examined rescue medication usage in relation to timeof day (over four 6-hour intervals) and elapsed treatment duration(number of days on the trial). These analyses generally showed a gradualdecrease in the amount of rescue medication usage as the number of dayson trial medication increased, across all treatment groups.Additionally, post hoc analyses demonstrated rescue medication usage waslower among Meloxicam Capsules subjects compared with placebo for mosttime intervals throughout the treatment period. Rescue medication usageduring the evening hours was lower for Meloxicam Capsules subjectscompared with placebo, with most robust differences noted for thosesubjects in the 10 mg treatment group.

An exploratory analysis evaluated whether the PK properties of MeloxicamCapsules might be associated with a measurable impact on analgesiafollowing administration of the morning dose at a time corresponding tothe observed maximum plasma concentration (2 hours). Subjects in theMeloxicam Capsules 5 mg and 10 mg treatment groups and the placebo groupassessed their OA pain using the 11-point NPRS on a single day within 1week of completion of the Week 2 Visit at predose, and 2-hour postdosetime points. Subjects in the Meloxicam Capsules 5 mg and 10 mg treatmentgroups demonstrated a greater percentage reduction in the NPRS scorecompared with placebo. Substantial differences vs placebo in the rawmean change and LS mean change in NPRS score from predose to postdoseassessment were noted in the Meloxicam Capsules 5 mg group; however,these changes were significant only for the LS Mean analysis forpercentage change (P=0.0294). The results for the sensitivity analysisof the exploratory efficacy analysis using BOCF imputation were similarto the first exploratory efficacy analysis.

Overall, once daily Meloxicam Capsules 5 mg and 10 mg were generallywell tolerated. The number and type of TEAEs that were reported duringthe conduct of the trial were expected and typical for this trialpopulation. A total of 113 subjects experienced at least 1 TEAE duringthe trial. A higher proportion of subjects in the placebo (32.3%)treatment group experienced at least 1 TEAE compared with the 5 mg(25.4%) and 10 mg (26.7%) groups. No subjects in any treatment groupexperienced an SAE, and no deaths occurred during the conduct of thistrial. A total of 3 subjects overall experienced TEAEs considered severein intensity; a higher proportion of subjects in the placebo treatmentgroup (1.5%) experienced severe TEAEs compared with the MeloxicamCapsules 5 mg (0.0%) and 10 mg (0.8%) groups.

Overall, headache was the most frequently reported TEAE in all subjects(2.7%). Headache and diarrhea were the most common TEAEs in the CombinedMeloxicam Capsules group (2.6%), followed by nausea (2.2%). A higherproportion of subjects in the combined Meloxicam Capsules group reportednausea (2.2%) and diarrhea (2.6%) when compared with subjects in theplacebo group (0.0% and 0.8%, respectively). Headache (3.8%) andabdominal discomfort (2.3%) occurred with higher frequency in theMeloxicam Capsules 10 mg group while exacerbation of OA (2.9%) wasobserved more frequently in the Meloxicam Capsules 5 mg group. All otherTEAEs appeared to be reported by similar proportions of subjects acrosstreatment groups.

Twelve subjects discontinued trial drug due to a TEAE. A total of 6subjects in the 2 active treatment groups and 6 subjects in the placebogroup experienced events leading to trial drug discontinuation.

Vital sign values, hematology laboratory values, urinalysis laboratoryvalues, physical examination findings, and ECG findings were generallynormal, stable, and similar across treatment groups. Clinicallysignificant changes in some chemistry laboratory values (alkalinephosphatase, ALT, AST, bilirubin, BUN, creatinine, glucose, andpotassium) were observed, some of which had TEAEs associated with them,but none of which were considered serious.

Overall, the primary, secondary, and post hoc analyses providesubstantial evidence of efficacy for Meloxicam Capsules 5 mg and 10 mgadministered once daily for the treatment of OA-related pain. Althoughresults indicating a dose response for Meloxicam were noted for some butnot for all efficacy assessments, evidence of a dose effect wasdemonstrated across multiple secondary and post hoc analyses includinguse of rescue medication, withdrawal due to lack of efficacy, a modifiedOMERACT-OARSI responder analysis, and clinician- and subject-reportedoutcomes.

Safety results indicate that Meloxicam Capsules 5 mg and 10 mg aregenerally well tolerated with a safety profile that is consistent withthe known safety profile of Meloxicam. Importantly, there were nosignificant cardiovascular, GI, or renal TEAEs of the type that havebeen associated with NSAID usage in any treatment group.

Taken together, the results of this trial highlight the treatmentbenefit of once daily Meloxicam Capsules 5 mg and 10 mg for thetreatment of pain associated with OA symptoms. Additionally, treatmentwith Meloxicam Capsules also appears to provide meaningful improvementsin other symptoms of OA, namely improvements in function, stiffness, andoverall status.

1. A unit dosage form of a pharmaceutical composition comprising 5 mg ofmeloxicam, wherein a single dose, upon oral administration to apopulation of healthy adults in the fasted state, provides a mean plasmaAUC (0-∞) of 7500-20000 h*ng/ml. 2.-12. (canceled)
 13. A unit dosageform comprising 10 mg of meloxicam, wherein a single dose, upon oraladministration to a population of healthy adults in the fasted state,provides a mean plasma AUC (0-∞) of 16000-44000 h*ng/ml. 14.-30.(canceled)